Based on our recent findings, we have raised two hypotheses which we propose to investigate under this grant. The first hypothesis proposes that Saccharomyces cerevisiae possesses a mammalian-like hormone and receptor system which is analogous to steroid hormone receptors in higher organisms. We propose that the estrogen binding protein (EBP), which we have demonstrated in S. cerevisiae cytosol, represents a hormone "receptor" and that the estrogenic substances we have detected in yeast and conditioned culture medium represent the endogenous ligand(s) for EBP or the "hormone". The specific goals of this section of the proposal include: (1) further characterization of EBP, particularly a determination of whether it is a DNA binding protein; (2) purification and identification of the various estrogenic substances in S. cerevisiae and elucidation of their synthetic pathway and regulation of their production and (3) an attempt to demonstrate a physiological bioresponse of the yeast to added estrogens or purified ligands. The second hypothesis to be examined is that yeast-produced estrogens contaminate food products and function as environmental estrogens. The specific goals of this section of the grant will be to ascertain whether biologically significant amounts of yeast-produced estrogens are present in yeast products including alcoholic beverages produced by yeast fermentation and various yeast extracts. Wine, beer, whiskey and yeast extracts for culture of microorganisms or as dietary supplements will be examined for estrogenic activity. We are intrigued by the possibility that yeast produced estrogenic substances in alcoholic beverages might contribute to the syndrome of feminization and hypogonadism characteristically found in alcoholic males with chronic liver disease. The long term goals of the project are to establish whether yeast has hormone-receptor systems which are similar to vertebrates and whether the yeast hormones in the environment gain access to human receptors and elicit estrogenic activity. The project will also shed light on the evolutionary origin of hormones, provide simple model systems for the study of hormone-action and has clinical relevance in a variety of ways including the possibility that yeast estrogens contribute to the hyperestrogenization syndrome seen in men with chronic alcoholism.